Copolymer Involving 2-Hydroxyethyl Methacrylate and 2-Chloroquinyl Methacrylate: Synthesis, Characterization and In Vitro 2-Hydroxychloroquine Delivery Application

The Poly(2-chloroquinyl methacrylate-co-2-hydroxyethyl methacrylate) (CQMA-co-HEMA) drug carrier system was prepared with different compositions through a free-radical copolymerization route involving 2-chloroquinyl methacrylate (CQMA) and 2-hydroxyethyl methacrylate) (HEMA) using azobisisobutyronitrile as the initiator. 2-Chloroquinyl methacrylate monomer (CQMA) was synthesized from 2-hydroxychloroquine (HCQ) and methacryloyl chloride by an esterification reaction using triethylenetetramine as the catalyst. The structure of the CQMA and CQMA-co-HEMA copolymers was confirmed by a CHN elementary analysis, Fourier transform infra-red (FTIR) and nuclear magnetic resonance (NMR) analysis. The absence of residual aggregates of HCQ or HCQMA particles in the copolymers prepared was confirmed by a differential scanning calorimeter (DSC) and XR-diffraction (XRD) analyses. The gingival epithelial cancer cell line (Ca9-22) toxicity examined by a lactate dehydrogenase (LDH) assay revealed that the grafting of HCQ onto PHEMA slightly affected (4.2–9.5%) the viability of the polymer carrier. The cell adhesion and growth on the CQMA-co-HEMA drug carrier specimens carried out by the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay revealed the best performance with the specimen containing 3.96 wt% HCQ. The diffusion of HCQ through the polymer matrix obeyed the Fickian model. The solubility of HCQ in different media was improved, in which more than 5.22 times of the solubility of HCQ powder in water was obtained. According to Belzer, the in vitro HCQ dynamic release revealed the best performance with the drug carrier system containing 4.70 wt% CQMA.

Effect of Amphiphilic Graft Co-Polymer Carrier on Solubility and Dissolution Enhancement of Ambrisentan

Aim: Ambrisentan is a endothelin type A selective receptor antagonist used in the management of pulmonary arterial hypertension. Ambrisentan is BCS Class II drug haves very poor solubility in water and shows incomplete absorption after oral administration. The present work was aimed to study the effect of amphiphilic graft co-polymer carrier on enhancement of solubility and dissolution rate of poorly water soluble drug ambrisentan. To improve the aqueous solubility of ambrisentan solid dispersion was formulated by using novel carrier amphiphilic graft co-polymer (Soluplus® ). Materials and Methods: Solid dispersion was prepared by kneading technique by utilizing various ratios of carrier. Obtained solid dispersions ware evaluated for solubility, percentage yield, drug content and in vitro dissolution study. Powder characterization was performed by infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction (XRD). Results: FTIR spectroscopy shows no interaction between drug and polymer. DSC study showed that endothermic peak of drug was completely disappeared in Solid dispersion suggesting complete miscibility of drug in Soluplus®. XRD study suggest the conversion of crystalline ambrisentan in to amorphous form. All solid dispersions prepared with Soluplus® as a carrier showed increase in solubility. Solubility of ambrisentan was found to be increased 7.17 fold in optimized SD formulation ASD5. In vitro dissolution study showed the faster drug release from SD formulation compare to its pure form. All solid dispersion formulation’s release more than 50% of drug in first 10 min. Conclusion: This study conclude that the preparation of amphiphilic graft co-polymer based solid dispersion prepared by kneading technique is found to be useful in enhancement the solubility and dissolution rate of ambrisentan.

The effect of spacers in dual drug-polymer conjugates toward combination therapeutic efficacy

Recently, a great effort has been made to perfect the therapeutic effect of solid tumor, from single-agent therapy to combined therapy and many other polymer-drug conjugations with dual or more anticancer agents due to their promising synergistic effect and higher drug level accumulation towards tumor tissues. Different polymer-drug spacers present diverse therapeutic efficacy, therefore, finding an appropriate spacer is desirable. In this study, dual drugs that are doxorubicin (DOX) and mitomycin C (MMC) were conjugated onto a polymer carrier (xyloglucan) via various peptide or amide bonds, and a series of polymers drug conjugates were synthesized with different spacers and their effect on tumor treatment efficacy was studied both in vitro and in vivo. The result shows that the synergistic effect is better when using different linker to conjugate different drugs rather than using the same spacer to conjugate different drugs on the carrier. Particularly, the finding of this works suggested that, using peptide bond for MMC and amide bond for DOX to conjugate dual drugs onto single XG carrier could improve therapeutic effect and synergy effect. Therefore, in polymer-pharmaceutical formulations, the use of different spacers to optimize the design of existing drugs to enhance therapeutic effects is a promising strategy.

Self-assembled multifunctional neural probes for precise integration of optogenetics and electrophysiology

Optogenetics combined with electrical recording has emerged as a powerful tool for investigating causal relationships between neural circuit activity and function. However, the size of optogenetically manipulated tissue is typically 1-2 orders of magnitude larger than that can be electrically recorded, rendering difficulty for assigning functional roles of recorded neurons. Here we report a viral vector-delivery optrode (VVD-optrode) system for precise integration of optogenetics and electrophysiology in the brain. Our system consists of flexible microelectrode filaments and fiber optics that are simultaneously self-assembled in a nanoliter-scale, viral vector-delivery polymer carrier. The highly localized delivery and neuronal expression of opsin genes at microelectrode-tissue interfaces ensure high spatial congruence between optogenetically manipulated and electrically recorded neuronal populations. We demonstrate that this multifunctional system is capable of optogenetic manipulation and electrical recording of spatially defined neuronal populations for three months, allowing precise and long-term studies of neural circuit functions.

Acclimatization studies for degradation of Acid Red 3BN dye and its treatment in moving bed biofilm reactor

In this study, acclimatization of microorganisms for the degradation of Acid Red 3BN dye bearing water (AR3BNDW) using activated sludge was performed in a cylindrical aerobic reactor. The initial value of chemical oxygen demand (COD), dye, and mixed liquor suspended solids (MLSS) of activated sludge were evaluated as 870.5, 80.6 and 1200 mg/L The experiments were performed at ambient temperature (25–35 °C) and the stabilization was achieved at 15 d. Maximum reduction of chemical oxygen demand (COD) and color were observed to be 94.2%, and 91% after 15 d of acclimatization. After completion of acclimatization process, degradation of dye was studied in moving bed biofilm reactor (MBBR). In the process, 38, 50, 68 and 76% color reduction were achieved with polymer carrier fill ratio (FR) of 40, 50, 60 and 70%, respectively in 24 h. For effluent flow rate of 180, 240, 300 and 360 mL/h, respectively, the dye reductions of 76, 60, 48 and 36% and COD reductions of 72, 58, 46 and 34% were achieved in 24 h

HPMA-Based Polymer Conjugates for Repurposed Drug Mebendazole and Other Imidazole-Based Therapeutics

Recently, the antitumor potential of benzimidazole anthelmintics, such as mebendazole and its analogues, have been reported to have minimal side effects, in addition to their well-known anti-parasitic abilities. However, their administration is strongly limited owing to their extremely poor solubility, which highly depletes their overall bioavailability. This study describes the design, synthesis, and physico-chemical properties of polymer-mebendazole nanomedicines for drug repurposing in cancer therapy. The conjugation of mebendazole to water-soluble and biocompatible polymer carrier was carried out via biodegradable bond, relying on the hydrolytic action of lysosomal hydrolases for mebendazole release inside the tumor cells. Five low-molecular-weight mebendazole derivatives, differing in their inner structure, and two polymer conjugates differing in their linker structure, were synthesized. The overall synthetic strategy was designed to enable the modification and polymer conjugation of most benzimidazole-based anthelmintics, such as albendazole, fenbendazole or albendazole, besides the mebendazole. Furthermore, the described methodology may be suitable for conjugation of other biologically active compounds with a heterocyclic N-H group in their molecules.

The Role of Polymer Carrier and Process Parameters for Small Molecule Drug Delivery via Blended Electrospinning

Delivery of therapeutic compounds to the diseased area in the body with minimized adverse effects is the underlying objective behind development of advanced drug delivery systems. Providing disease-specific release patterns is the ultimate goal of any drug delivery system. Electrospinning has been widely used for nanofiber fabrication. Having high aspect ratio and similarity to the extracellular matrix in the body make electrospun nanofibers a great candidate to be used as drug delivery implants. In this study, we report electrospinning to be a tunable technique capable of providing engineered, disease-specific drug release patterns. Using “one factor at a time” and “central composite design” techniques, we respectively demonstrate flow rate and applied voltage to be the two most significant parameters (with [Formula: see text]-values of 512.48 and 42.31) affecting the final fiber diameter, and capillary-to-collector distance as the least important one, by evaluating their influence, individually and combined, on the morphology of electrospun Poly (Lactide-co-Glycolide acid) nanofibers. Using the same two techniques, we also show that hydrophobicity of the polymeric fibrous scaffold, measured by water contact angle (WCA) with the [Formula: see text]-value of 376.44, is the main factor to consider when designing an electrospun fibrous drug delivery system for a specific disease, while fiber diameter can further modulate the release pattern of the drug from hydrophobic polymeric nanofibers. We finally support our hypothesis by comparing our findings with analysis of data derived from the literature. Taken together, our findings suggest electrospinning to be a tunable technique capable of providing various release patterns for any small molecular weight drug on the basis of the requirements of the diseases to be treated.

Click chemistry-based pre-targeting cell delivery for cartilage regeneration

A fraction of the OA patient population is affected by post-traumatic osteoarthritis (PTOA) following acute joint injuries. Stopping or reversing the progression of PTOA following joint injury could improve long-term functional outcomes, reduced disability, and medical costs. To more effectively treat articular cartilage injury, we have developed a novel cell-based therapy that involves the pre-targeting of apoptotic chondrocytes and the delivery of healthy, metabolically active chondrocytes using click chemistry. Specifically, a pre-targeting agent was prepared via conjugating apoptotic binding peptide (ApoPep-1) and trans-cyclooctene (TCO) onto polyethylene glycol (PEG) polymer carrier. The pre-targeting agent would be introduced to injured areas of articular cartilage, leading to the accumulation of TCO groups on the injured areas from actively binding to apoptotic chondrocytes. Subsequently, methyltetrazine (Tz)-bearing chondrocytes would be immobilized on the surface of TCO-coated injured cartilage via Tz-TCO click chemistry reaction. Using an ex vivo human cartilage explant PTOA model, the effectiveness of this new approach was evaluated. Our studies show that this novel approach (Tz-TCO click chemistry) significantly enhanced the immobilization of healthy and metabolically active chondrocytes to the areas of apoptotic chondrocytes. Histological analyses demonstrated that this treatment regimen would significantly reduce the area of cartilage degeneration and enhance ECM regeneration. The results support that Tz-TCO click chemistry-mediated cell delivery approach has great potential in clinical applications for targeting and treatment of cartilage injury.

Quercetin Nanoparticle Ameliorates Lipopolysaccharide-Triggered Renal Inflammatory Impairment by Regulation of Sirt1/NF-KB Pathway

As a conventional complication of sepsis, acute kidney injury (AKI) is characterized by high incidence and mortality. Effective management methods are still lacking. Quercetin belongs to a kind of flavonoids that exerts many functions, for example anti-inflammation and anti-fibrosis. However, its function in sepsis AKI is uncertain. Our study therefore set out to assess the function of quercetin in AKI mice model induced by lipopolysaccharide (LPS) and human proximal tubular cells (HK-2), including the potential mechanisms. Quercetin was loaded onto a biodegradable polymer carrier (nanoparticle) to enhance its bioavailability. The data showed that quercetin administration strikingly improved renal dysfunction and ameliorated tubular injury caused by LPS in mice. In mice model and in cultured cells, quercetin pretreatment obviously restrained LPS-triggered cell apoptosis and inflammation, including generation of various cytokines. Moreover, the results from mice model and cell model showed that quercetin could diminish IκBα and p65 phosphorylation after LPS treatment. The most significant observation of this study was that quercetin elevated the expression of Sirt1. Transfection of Sirt1 specific shRNA mitigated the suppression of quercetin on cell apoptosis, inflammation and of NF-κB activation triggered by LPS. Therefore, these sequels indicate that quercetin protects against sepsis-associated AKI by upregulation Sirt1 expression through quenching NF-κB activation and may be an encouraging therapeutic agent for patients with sepsis-associated AKI.